Elevated LIM kinase 1 in nonmetastatic prostate cancer reflects its role in facilitating androgen receptor nuclear translocation

Mardilovich, K., Gabrielsen, M. , McGarry, L., Orange, C., Patel, R., Shanks, E., Edwards, J. and Olson, M. F. (2015) Elevated LIM kinase 1 in nonmetastatic prostate cancer reflects its role in facilitating androgen receptor nuclear translocation. Molecular Cancer Therapeutics, 14(1), pp. 246-258. (doi: 10.1158/1535-7163.MCT-14-0447)

Abstract

Prostate cancer affects a large proportion of the male population, and is primarily driven by androgen receptor (AR) activity. First-line treatment typically consists of reducing AR signaling by hormone depletion, but resistance inevitably develops over time. One way to overcome this issue is to block AR function via alternative means, preferably by inhibiting protein targets that are more active in tumors than in normal tissue. By staining prostate cancer tumor sections, elevated LIM kinase 1 (LIMK1) expression and increased phosphorylation of its substrate Cofilin were found to be associated with poor outcome and reduced survival in patients with nonmetastatic prostate cancer. A LIMK-selective small molecule inhibitor (LIMKi) was used to determine whether targeted LIMK inhibition was a potential prostate cancer therapy. LIMKi reduced prostate cancer cell motility, as well as inhibiting proliferation and increasing apoptosis in androgen-dependent prostate cancer cells more effectively than in androgen-independent prostate cancer cells. LIMK inhibition blocked ligand-induced AR nuclear translocation, reduced AR protein stability and transcriptional activity, consistent with its effects on proliferation and survival acting via inhibition of AR activity. Furthermore, inhibition of LIMK activity increased αTubulin acetylation and decreased AR interactions with αTubulin, indicating that the role of LIMK in regulating microtubule dynamics contributes to AR function. These results indicate that LIMK inhibitors could be beneficial for the treatment of prostate cancer both by reducing nuclear AR translocation, leading to reduced proliferation and survival, and by inhibiting prostate cancer cell dissemination.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Orange, Miss Clare and Edwards, Professor Joanne and Gabrielsen, Dr Mads and Mardilovich, Dr Katerina and Shanks, Dr Emma and Patel, Dr Rachana and McGarry, Ms Lynn and Olson, Professor Michael
• Authors: Mardilovich, K., Gabrielsen, M., McGarry, L., Orange, C., Patel, R., Shanks, E., Edwards, J., and Olson, M. F.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Molecular Cancer Therapeutics
• Publisher: American Association for Cancer Research
• ISSN: 1535-7163
• ISSN (Online): 1538-8514
• Published Online: 24 October 2014